1. Field of the Invention
The present invention generally relates to the field of therapeutics. Specifically, the present invention relates to therapeutic compositions comprising inhibitors of prolactin or prolactin receptor function, said therapeutic compositions being suitable for use in treating pain. The present invention further relates to methods for the manufacture and use of said therapeutic compositions. The present invention relates yet further to methods for assessing the severity of pain and/or diagnosing pain disorders in subjects by determining the amount of prolactin present in a biological sample.
2. Description of the Related Art
Trigeminal pain represents a major category of pain disorders and is reported frequently in pain patients, particularly given its comparatively low representation of the total body surface area. (Martin 1986; Khouzam 2000; Welch 2001). From a public health perspective, diagnosis and treatment of trigeminal pain disorders represent a major clinical challenge. Some disorders are relatively rare but are characterized as extremely intense devastating episodes of pain (e.g., trigeminal neuralgia (TN) (Zakrzewska 1996; Devor, Amir et al. 2002; Zakrzewska 2002; Zakrzewska 2002; Kapur, Kamel et al. 2003), others disorders are more common and can be acute-to-chronic periods of persistent aching pain (e.g., temporomandibular disorders, TMD, (Lipton, Ship et al. 1993; Carlsson and LeResche 1995; LeResche, Saunders et al. 1997), Yet other conditions are relatively common occurrences of moderate-to-severe pain due to orofacial infection and inflammation (e.g., odontogenic pain). Many other pain disorders also occur in other body regions and include pain from fibromyalgia, cancer, arthritis, surgery, and other disorders or conditions.
Numerous studies have demonstrated that women are at increased risk for many pain disorders. Moreover, several of these conditions are exacerbated during the menstrual cycle or during episodes of altered circulating levels of estrogens or other steroids (Somerville, 1975; LeResche, 1997; Isselee et al., 2001; Isselee et al., 2002). Although gender bias is clearly evident for TMD (LeResche, Saunders et al. 1997; Warren and Fried 2001; Huang, LeResche et al. 2002; Johansson, Unell et al. 2003) and trigeminal neuralgia (Katusic, Beard et al. 1990; Kitt, Gruber et al. 2000), other studies have indicated that women are at increased risk for pain after oral surgery, (Gear, Miaskowski et al. 1996; Gordon, Brahim et al. 1999) periodontal treatment (Karadottir, Lenoir et al. 2002), knee surgery (Asano, Muneta et al. 2002), other surgical procedures, (Kalkam, Visser et al. 2003) musculoskeletal pain in the neck (Chiu, Ku et al. 2002), hips (Tuchsen, Hannerz et al. 2003), hands (Gerr, Marcus et al. 2002), and elsewhere (Barsky, Peekna et al. 2001; Kostova and Koleva 2001), and disorders including fibromyalgia (Yunus 2002; Staud, Robinson et al. 2003), post-herpetic neuralgia (Bowsher 1999), migraine (Martin, Wernke et al. 2003), irritable bowel syndrome (Borum 2002),. and cancer pain (Bernabei, Gambassi et al. 1998). Thus, studies from multiple pain disorders indicate that patient gender may, at least in part, be a risk factor for numerous acute and chronic pain conditions. While the mechanisms for these gender differences in pain responsiveness are numerous, complex and are far from being understood, many studies have identified the important role played by sex hormones, and in particular estrogen, on pain responses.
Relationship Between Estrogen and Prolactin
PRL was originally discovered as a protein hormone, derived from pituitary lactotrophs, that acted to regulate lactation. However, considerable research has now identified several post-translationally modified forms of PRL that vary based on size, phosphorylation or glycosylation (Freeman, Kanyicska et al. 2000; Walker 2001). In the rat, ˜90-95% of pituitary PRL is either the unmodified or phosphorylated PRL, and the unmodified form constitutes about 60-75% of total PRL (Oetting and Walker 1986; Ho, Kawaminami et al. 1993; Walker 2001). In general, the unmodified PRL acts as an agonist, while the form PRL that is phosphorylated on S179 acts as a partial agonist or full antagonist (Walker 2001; Goffin, Bernichtein et al. 2003; Wu, Coss et al. 2003; Xu, Wu et al. 2003) in many situations, depending on the experimental systems being tested (Bernichtein, Kinet et al. 2001). This difference appears to be due to agonist-directed signaling of the same PRL receptor (Coss, Kuo et al. 1999). Equally important, many non-pituitary cells express PRL including the CNS, immune cells, endothelium, kidney and uterus. In many of these tissues, PRL is thought to play a major autocrine/paracrine function since both PRL and the prolactin receptor (PRL-R) are expressed in the same cell/tissue. Evidence supporting the hypothesis that PRL exerts a local autocrine/paracrine function has been gathered for the mammary gland, endothelium, lymphocytes, knee joints and several types of cancers (Nagafuchi, Suzuki et al. 1999; Nowak, Mora et al. 1999; Bhatavdekar, Patel et al. 2000; Urtishak, McKenna et al. 2001; Ben-Jonathan, Liby et al. 2002; Corbacho, Martinez De La Escalera et al. 2002; Ogueta, Munoz et al. 2002; Goffin, Bernichtein et al. 2003; Naylor, Lockefeer et al. 2003).
Both in vivo and in vitro studies indicate that application of estrogen or cyclic increases in endogenous estradiol leads to a rapid, non-genomic release of PRL via activation of calcium channels (Christian and Morris 2002; Brown, Janik et al. 2004; Szawka and Anselmo-Franci 2004; Bulayeva, Wozniak et al. 2005). Indeed, an estradiol-induced PRL surge accompanies the proestrous LH surge in several species (Skinner and Caraty 2003). The rapid effect of estradiol on PRL release is believed to be mediated by estrogen receptors (ER) located on the plasma membrane since the estradiol effect is blocked by application of an antibody (presumably restricted to the extracellular space) that is directed against a hinge element of the ER (Watson, Norfleet et al. 1999; Norfleet, Clarke et al. 2000).
While acute estradiol exposure rapidly evokes PRL release, a more prolonged exposure increases PRL expression (i.e. transcription). This effect of estradiol on PRL expression has been demonstrated in several cell types (Watters, Chun et al. 2000; Oomizu, Boyadjieva et al. 2003; Fujimoto, Igarashi et al. 2004). In rat pituitary cultures, the estradiol-induced upregulation of PRL mRNA is mediated by the MAP kinase signaling pathway since PRL upregulation is blocked by pretreatment with the MAPK kinase inhibitors PD98059 and UO126 (Watters, Chun et al. 2000).
Prolactin Receptors and Associated Signaling Pathways
The PRL receptor (PRL-R) belongs to the class I cytokine receptor super-family. The PRL-R is transcribed from a single gene of the genome. Alternative splicing of the PRL-R gene generates a long form (L-PRL-R) and at least three short forms (S1-, S2- and S3-PRL-R) (Hovey, Trott et al. 2001). The expression of these forms of the PRL-R is tissue specific (Hovey, Trott et al. 2001; Kinoshita, Yasui et al. 2001; Yamamoto, Wakita et al. 2003) and differential expression is observed in different brain regions (Pi and Grattan 1998; Bakowska and Morrell 2003). The 5′-untranslated region of PRL-R mRNA also contains at least four alternative first exons (1A, B, C; aka E1(1), E1(2), E1(3) and E1(4)) that are expressed in a tissue-specific fashion (Tanaka, Hayashida et al. 2002). In addition, estradiol upregulates PRL-R transcripts (Leondires, Hu et al. 2002) and studies evaluating estradiol upregulation of PRL-R in rat brain report an increase in transcripts containing exons 1A and 1C (Pi, Zhang et al. 2003). Further, the relative expression of the long and short forms of PRL-R is altered over the estrous cycle in sheep ovaries (Picazo, Garcia Ruiz et al. 2004) and female rat brain (Pi and Voogt 2002). One study has reported the expression of PRL-R in fetal trigeminal and dorsal root ganglia (Royster, Driscoll et al. 1995).
PRL receptors regulate a variety of intracellular signaling cascades that differ depending upon the cell type examined. The best-studied signaling systems are mediated through tyrosine kinase pathways. In a prostate carcinoma cell line, application of PRL leads to rapid tyrosine kinase signaling that is blocked by the tyrosine kinase inhibitors genistein, herbimycin A and lavandustine A (Van Coppenolle, Skryma et al. 2004). In the MCF-7 breast tumor cell line, activation of PRL-R leads to signaling primarily via Janus kinase/signal transducer and activator of transcription 5 (JAK/STAT5) and ERK1/2, although signaling via c-Src, phosphatidylinositol 3′-kinase, (phospholipase C-gamma PLCγ), protein kinase C, and other MAPKs were shown to contribute to maximal signaling (Dogusan, Hooghe et al. 2001; Fresno Vara, Caceres et al. 2001; Ahonen, Harkonen et al. 2002; Gutzman, Rugowski et al. 2004). Some studies on cell lines have shown that application of PRL stimulates Ca2+ entry and intracellular Ca2+ mobilization via a tyrosine kinase-dependent mechanism (Sorin, Vacher et al. 2000; Ducret, Boudina et al. 2002). Studies in other cell lines have confirmed activation of many of these kinases although the relative importance of various signaling pathways activated by PRL-R are dependent upon the cell type examined or the measure employed (Cheng, Zhizhin et al. 2000; Goupille, Barnier et al. 2000; Gubbay, Critchley et al. 2002; Amaral, Ueno et al. 2003; Amaral, Cunha et al. 2004; D'Isanto, Vitiello et al. 2004; Dominguez-Caceres, Garcia-Martinez et al. 2004). Fewer studies have evaluated whether the different forms of PRL-R activate different signaling pathways (Binart, Imbert-Bollore et al. 2003). It was demonstrated that the long form of the PRL-R can signal via all known PRL evoked pathways, whereas the short forms of PRL-R, which have a truncated cytoplasmic domain, have a much more restricted signaling repertoire that includes PKC and PLCγ (Schuler, Lu et al. 2001; Wallaschofski, Kobsar et al. 2003).
Transient Receptor Potential Vanniloid Type-1 (TRPV1) in Pain
The subclass of nociceptors expressing the capsaicin receptor (i.e., TRPV1 aka VR1) plays a key role in the development of pain. Animals with genetic deletion of the VR1 gene display reduced responses to thermal inflammatory hyperalgesia or to certain chemical stimuli (Caterina, Schumacher et al. 1997; Davis, Gray et al. 2000). In addition, capsaicin desensitization procedures significantly reduced behavioral responses to inflammatory injury in rats or neuropathic pain in humans (McCleane 1999; Ikeda, Ueno et al. 2001). Other studies have also lent support to the hypothesis that the TRPV1-positive subclass of nociceptors contributes to the development of inflammatory pain (Carlton and Coggeshall 2001; Chuang, Prescott et al. 2001; Kamei, Zushida et al. 2001). Further, the TRPV1-positive subclass of nociceptors mediates thermal hyperalgesia and dynamic (i.e., stroking with cotton wisp) but not static (i.e., von Frey filaments) mechanical allodynia in neuropathic pain (Ossipov, Bian et al. 1999; Chuang, Prescott et al. 2001). Collectively, these studies indicate that the TRPV1-expressing class of nociceptors is a major sensory system for transduction of noxious peripheral stimuli.